A regioselective addition of nucleophiles to monocyclic 1,2-thiazinylium perchlorate: A novel precursor of 6-substituted 1,2-thiazines

Article abstract of DOI:10.1016/S0040-4020(01)00908-5

The nucleophilic addition reactions of 4,5-diphenyl-1,2-thiazinylium perchlorate 1 regioselectively proceeded to give 6-alkoxy-3a-c and 6-alkyl-1,2-thiazines 3e-f, 4f, 3i-j in good to high yields. The Friedel-Crafts type reaction with arenes also afforded 6-aryl adducts 6a-c.

Full text of DOI:10.1016/S0040-4020(01)00908-5

TETRAHEDRON
Pergamon
Tetrahedron 57 92001) 8965±8969
A regioselective addition of nucleophiles to monocyclic
1,2-thiazinylium perchlorate: a novel precursor
of 6-substituted 1,2-thiazines
Hiroshi Shimizu,a,p Naoyuki Okadab and Mitsuhiro Yoshimatsub
aGifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
bDepartment of Chemistry, Faculty of Education, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received 18 July 2001; accepted 7 September 2001
AbstractÐThe nucleophilic addition reactions of 4,5-diphenyl-1,2-thiazinylium perchlorate 1 regioselectively proceeded to give 6-alkoxy-
3a±c and 6-alkyl-1,2-thiazines 3e±f, 4f, 3i±j in good to high yields. The Friedel±Crafts type reaction with arenes also afforded 6-aryl
adducts 6a±c. q 2001 Elsevier Science Ltd. All rights reserved.
Recently, we have reported novel hetero Diels±Alder
reactions of 1,2-thiazinylium salt as a good dienophile.
The inter-element, NvS1 bond of the dibenzo[c,e]-
[1,2]thiazinylium salt has reacted with the 1,3-butadienes
to give the cyclic sulfonium salts via the polar [2114]
cycloaddition reaction,1 while the reaction site of the mono-
cyclic 4,5-diphenyl-1,2-thiazinylium perchlorate 1 has not
been the NvS1 bond of 1, but the CvS1 bond 9Scheme 1).2
The different reactivity of the cycloaddition reactions
between the dibenzo-1,2-thiazinylium salt and the mono-
cyclic derivative could be explained in terms of LUMO
coef®cients of the thiazinylium salt obtained from the
PM3 calculation. The 1,2-thiazinylium salt 1 is a unique
heterocyclic compound; however, it has not been charac-
terized except in the polar [2114] cycloadditions. Our
next interest is the reaction of monocyclic 1,2-thiazinylium
salt 1 having several reaction sites with nucleophiles. The
regioselective addition of the thiazinylium salt would
provide various 1,2-thiazines, which would be easily trans-
formed into the functionalized 1,2-thiazinylium salts as new
heterocyclic compounds with the biological interests.3 We
describe herein the regioselective additions of 1,2-thiazinyl-
ium salts, providing various 1,2-thiazines, and attempts at
preparation of more functionalized 1,2-thiazinylium salts.
1.Results and discussion
We ®rst examined the reaction of 1 with alkoxide nucleo-
philes. Two equivalents of NaOMe in MeOH gave
6-methoxy-1,2-thiazine 3a in 94% yield. The structure
1
was determined by the H NMR spectral data, showing
the methoxy protons at d 3.44, the 6-methine proton at d
5.16, the 3-imine proton at d 8.37, and the 13C NMR spectral
data exhibiting the 6-acetal carbon at d 80.07 9d).
The reactions with other alkoxides such as NaOEt
and NaOiPr were also examined and 6-ethoxy- 3b and
Table 1. Reaction of 1,2-thiazinylium salt 1 with nucleophiles
Entry
Nucleophile 9equiv.)
NaOMe 92)
NaOEt 92)
Solvent Products 9R) 9% Yield)
1
2
3
4
5
6
7
8
9
MeOH 3a 9OMe) 994)
EtOH
iPrOH
3b 9OEt) 990)
3c 9OiPr) 9quant)
NaOiPr 93)
KOt Bu92)
CH2vCPh9OTMS) 91.2)
tBuOH Complex mixture
MeCN
CH2vC9SEt)9OTMS) 91.5) MeCN
3e 9CH2COPh) 970)
3f 9CH2COSEt) 942)
4f 9CH2COSEt) 958)
Complex mixture
3h 9SPh) 977)
3i 9CH9CO2Et)2) 993)
3j 9CH9COMe)2 9quant)
Scheme 1.
CH2vC9SEt)9OTMS) 95)
Et2NH 91.2)
NaSPh 91.2)
MeCN
MeCN
THF
THF
THF
Keywords: 1,2-thiazinylium perchlorate; novel precursor; 1,2-thiazines.
Corresponding author. Tel.: 181-58-237-3931; fax: 181-58-237-5979;
e-mail: shimizu@gifu-pu.ac.jp
10NaCH9CO 2Et)2 91.2)
11 NaCH9COMe)2 91.5)
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020901)00908-5

8966
H. Shimizu et al. / Tetrahedron 57 12001) 8965±8969
on the 6-position of the 1,2-thiazinylium salt to give
6-9phenylsulfanyl)-1,2-thiazine 3h, diethyl 91,2-thiazin-6-
yl)malonate 3i and 91,2-thiazin-6-yl)pentane-2,4-dione 3j
9entries 9±11).
We investigated the reaction of the products with acid
9Scheme 2). Treatment of 6-methoxy-1,2-thiazine 3a with
HClO4 provided the thiazinylium salt 1 in 88% yield.
Similarly, other 6-alkoxy-1,2-thiazines 3b and 3c also
provided the salt 1 in good yields on treatment with the
acid. The addition of SO2Cl2 to an ethereal solution of 3h
provided a yellow suspension, which was successively
treated with 70% HClO4 to give the salt 1 via the replace-
ment of the counter anion of an in situ formed 1,2-thiazinyl-
ium chloride 5 from chloride to perchlorate.
Scheme 2. Reagent: i, 70% HClO4; ii, SO2Cl2.
6-isopropoxy-1,2-thiazines 3c were obtained in high yields,
respectively, as shown in Table 1 9entries 2 and 3);
however, 3c was found to be labile at room temperature to
polymerize. KOtBu gave a complex mixture 9entry 4). Next,
we performed the reaction with silyl enol ethers as soft
carbon nucleophiles. 1-Phenyl-1-9trimethylsiloxy)ethylene
gave alkylated product 3e in 70% yield 9entry 5). Further,
S-ethyl ketene thioacetal afforded 6-alkyl-1,2-thiazine 3f.
Interestingly, the reaction with a large excess of the acetal
gave 3,6-dialkyl-1,2-thiazine 4f in good yield 9entries 6 and
7). However, a large excess of 1-phenyl-1-9trimethylsiloxy)-
ethylene gave no dialkylated 1,2-thiazine. These results
might be explained in terms of higher nucleophilicity of
S-ethyl ketene thioacetal. Other nucleophiles also reacted
We also performed the Friedel±Crafts type reaction of the
1,2-thiazinylium salt 1 with arenes 9Table 2). On treatment
with 1,2,3-trimethoxybenzene 92 equiv.) in ClCH2CH2Cl at
838C, the salt 1 underwent nucleophilic addition reaction at
6 position to give 6-92,3,4-trimethoxyphenyl)-1,2-thiazine
6a in 31% yield. The reaction site of the 1,2,3-trimethoxy-
1
benzene was found to be the 4-position by the H NMR
spectral data of 6a, which show the two aromatic protons
of the 2,3,4-trimethoxyphenyl group at d 6.61 9d, Jˆ9 Hz)
and 6.99 9d, Jˆ9 Hz) as an AB quartet. 1,2-Dimethoxy-
benzene also reacted with 1 to give 6-93,4-dimethoxy-
phenyl)-1,2-thiazine 6b in 39% yield, while anisole and
benzene did not react, and the salt 1 was recovered
Table 2. Reactions of 1,2-thiazinylium salt 1 with arenas
Entry
Arene 9equiv.)
Solvent
Product 9Ar) 9% Yield)
1
2
3
4
5
6
7
1,2,3-Trimethoxybenzene 91.2)
1,2-Dimethoxybenzene 92)
Anisole 95)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
Neat
ClCH2CH2Cl
ClCH2CH2Cl
CH3CN
6a 92,3,4-trimethyoxyphenyl) 931)
6b 93,4-dimethoxyphenyl) 939)
Recovery
Recovery
Complex mixture
Benzene
Thioanisole 95)
Thiophene 92)
Furan 92)
Complex mixture
6c 92-furyl) 946)
Scheme 3. Reagent: i, SO2Cl2/70% HClO4.

H. Shimizu et al. / Tetrahedron 57 12001) 8965±8969
8967
pressure. The residue was puri®ed by preparative TLC on
silica gel eluting with hexane±ethyl acetate 910:1) to give
6-methoxy-4,5-diphenyl-6H-1,2-thiazine 3a 9114 mg, 94%)
as brown powders, mp 110±1138C 9dec.), IR 9KBr, cm21):
14509N vCH), 1066 9ether). 1H NMR 9CDCl3) d: 3.44 93H,
s, Me), 5.16 91H, s, 6-H), 7.13±7.25 910H, m, ArH), 8.37
91H, s, 3-H). 13C NMR 9CDCl3) d: 53.01 9q), 80.07 9d),
127.86 9d), 128.33 9d), 128.42 9d£2), 128.58 9d£2),
128.96 9s), 129.76 9d£2), 130.31 9d£2), 131.49 9s), 138.58
9s), 138.85 9s), 155.97 9d). MS m/z: 281 9M1). Anal. calcd
for C17H15NOS: C, 72.57; H, 5.37; N, 4.98. Found: C, 72.63;
H, 5.45; N, 4.98.
Scheme 4.
unchanged, and thioanisole and thiophene gave complex
mixtures. The regioselective reaction with furan gave
6-92-furyl)-1,2-thiazine 6c in 46% yield 9entry 5).
2.1.2. With NaOEt. A solution of NaOEt 91 mmol) in EtOH
91 ml) was added dropwise to a stirred suspension of 1,2-
thiazinylium perchlorate 1 9175 mg, 0.5 mmol) in EtOH
92 ml). The work-up as above gave 6-ethoxy-4,5-diphenyl-
6H-1,2-thiazine 3b 9148 mg, 90%) as an oil, IR 9®lm,
We next investigated the transformation of the 6-alkylated 3
or 6-arylated 1,2-thiazines 6 to the corresponding 6-substi-
tuted 1,2-thiazinylium salts. The treatment of 3e with
SO2Cl2/70% HClO4, under the conditions similar to those
for the synthesis of 1, afforded the 6-91-chloro-1-phenacyl-
idene)-1,2-thiazine 7 in 58% yield as an E,Z mixture, and
not 8 9Scheme 3). The plausible mechanism for the forma-
tion of 7 is shown in Scheme 3. The reaction with SO2Cl2
would afford the 1,2-thiazinylium chloride 9, which easily
undergoes chlorination of the a-position to the carbonyl
group to form 10. The acidic hydrogen of the chloride 10
would be abstracted by chloride ion to give the phenacyl-
idene derivative 7. The treatment of 6-ary-1,2-thiazine 6b
with SO2Cl2/70% HClO4, however, quantitatively afforded
the 4,5,6-triaryl-1,2-thiazinylium perchlorate 11 as stable
white needles 9Scheme 4).
1
cm21): 14409N vCH), 1040 9ether). H NMR 9CDCl3) d:
1.28 93H, t, Jˆ7 Hz, Me), 3.47±3.55 91H, m, CHH), 3.87±
3.95 91H, m, CHH), 5.22 91H, s, 6-H), 7.11±7.27 910H, m,
ArH), 8.36 91H, s, 3-H). 13C NMR 9CDCl3) d: 15.21 9q),
61.32 9t), 78.409d), 127.75 9d), 128.21 9d), 128.35 9d £2),
128.48 9d£2), 129.09 9s), 129.68 9d£2), 130.32 9d£2),
131.32 9s), 138.609s), 139.03 9s), 155.87 9d). High resolu-
tion mass spectrum, m/z, 295.1037 9calcd for C18H17NOS,
295.1031).
2.1.3. With NaOiPr. A solution of NaOiPr 91.5 mmol) in
iPrOH 91 ml) was added dropwise to a stirred suspension of
1 9175 mg, 0.50 mmol) in iPrOH 92 ml) at 08C. The work-up
as above afforded 6-isopropyloxy-4,5-diphenyl-6H-1,2-
thiazine 3c 9155 mg, quant.) as an oil, IR 9®lm, cm21):
11209ether). 1H NMR 9CDCl3) d: 1.23 93H, d, Jˆ6 Hz,
Me), 1.27 93H, d, Jˆ6 Hz, Me), 4.09±4.22 91H, m,
CH9Me)2), 5.26 91H, d, Jˆ1 Hz, 6-H), 7.12±7.27 910H,
m, ArH), 8.4091H, s, 3-H). This compound was labile at
room temperature to give a polymer.
2.Experimental
Mps were determined on a Yanagimoto micro-melting point
apparatus and are uncorrected. Elemental analyses were
performed at the Microanalytical Laboratory of Gifu
1
Pharmaceutical University. H 9400 MHz) and 13C 9100
MHz) NMR spectra were determined with a Varian Inova
400 9400 MHz) spectrometer at the Center of Instrumen-
tation of Gifu University. Chemical shifts are expressed in
parts per million 9ppm) with respect to tetramethylsilane as
the internal standard. Splitting patterns are designated as
follows: s, singlet; d, doublet; t, triplet; q, quartet. IR spectra
were recorded on a JASCO IR A-100 infrared spectrometer.
EI Mass spectra 9MS) were obtained using a JMS-SX102A
spectrometer with a direct-insertion probe at an ionization
voltage of 70eV. Preparation of 4,5-diphenyl-1,2-thiazinyl-
ium perchlorate 1 was performed according to our previous
report.2
2.1.4. With 1-phenyl-1-1trimethylsilyloxy)ethylene. A
THF solution of Bu4NF 91.00 M, 4±5 drops) was added
dropwise to a stirred mixture of 1 91.00 g, 2.86 mmol) and
1-phenyl-1-trimethylsilyloxyethylene 9660mg, 3.43 mmol)
in dry MeCN 93 ml) and the reaction mixture was stirred for
0.5 h. The reaction mixture was poured into a sat. NaHCO3
solution and extracted with ethyl acetate. The extract was
washed with water, dried over MgSO4, and evaporated. The
residue was puri®ed by column chromatography on silica
gel eluting with hexane±ethyl acetate 910:1) to afford
6-phenacyl-4,5-diphenyl-6H-1,2-thiazine 3e 9744 mg,
70%) as yellow prisms, mp 142±1458C 9dec.) 9from
hexane±CH2Cl2), IR 9KBr, cm21): 16709CO). 1H NMR
9CDCl3) d: 3.12 91H, dd, Jˆ18 and 3 Hz, CHH), 3.81
91H, dd, Jˆ18 and 10Hz, CH H), 4.46 91H, dd, Jˆ10and
3 Hz, 6-H), 7.11±7.25 910H, m, ArH), 7.43±7.47 92H, m,
ArH), 7.54±7.58 91H, m, ArH), 7.93±7.96 92H, m, ArH),
8.28 91H, s, 3-H). 13C NMR 9CDCl3) d: 37.74 9d), 40.81 9t),
127.67 9d), 128.34 9d£2), 128.45 9d), 128.49 9d£2), 128.68
9d£2), 128.84 9d£2), 129.79 9d£2), 129.92 9d£2), 131.09
9s), 131.65 9s), 133.68 9d), 136.96 9s), 138.41 9s), 138.45 9s),
156.68 9d), 196.73 9s). MS m/z: 369 9M1). Anal. calcd for
C24H19NOS: C, 78.02; H, 5.18; N, 3.79. Found: C, 77.75; H,
5.38; N, 3.74.
2.1. Reactions of 4,5-diphenyl-1,2-thiazinylium
perchrolate 1 with nucleophiles
2.1.1. With NaOMe. A solution of NaOMe 98.58 mmol) in
MeOH 98.6 ml) was added dropwise to a stirred suspension
of 1,2-thiazinylium perchlorate 1 9150mg, 0.43 mmol) in
dry MeOH 91.5 ml) and the mixture was stirred for 30min at
room temperature. The solvent was removed under reduced
pressure. The residue was poured into water 950ml) and the
organic layer was separated and the aqueous layer was
extracted with ether. The combined organic layer was
dried over MgSO4. The solvent was removed under reduced

8968
H. Shimizu et al. / Tetrahedron 57 12001) 8965±8969
2.1.5. With 1-ethylthio-1-1trimethylsilyloxy)ethylene.
Under an Ar atmosphere, a solution of 1-ethylthio-1-
9trimethylsilyloxy)ethylene 976.0mg, 0.43 mmol) in dry
CH2Cl2 90.5 ml) was added dropwise to a stirred solution
of 1 9100 mg, 0.29 mmol) in dry CH2Cl2 91 ml) and the
mixture was stirred for 0.5 h. The reaction mixture was
poured into a sat. NaHCO3 solution and the organic layer
was separated. The water layer was extracted with ethyl
acetate. The combined organic layer was washed with
water, dried over MgSO4, and evaporated in vacuo. The
residual oil was subjected to preparative TLC on silica gel
with hexane±ethyl acetate 93:1) to give 6-9ethylthio)carbo-
nylmethyl-4,5-diphenyl-6H-1,2-thiazine 3f 942.0mg, 42%)
as an oil, IR 9®lm, cm21): 16709CO). 1H NMR 9CDCl3) d:
1.27 93H, t, Jˆ8 Hz, Me), 2.86±2.96 93H, m, CHHCO1
SCH2), 3.1091H, dd, Jˆ16 and 10Hz, CH HCO), 4.19
91H, dd, Jˆ10and 4 Hz, 6-H), 7.09±7.13 92H, m, ArH),
7.16±7.19 96H, m, ArH), 7.20±7.26 92H, m, ArH), 8.25
91H, s, 3-H). 13C NMR 9CDCl3) d: 14.81 9q), 23.96 9t),
38.96 9d), 45.94 9t), 127.75 9d), 128.49 9d£3), 128.72
9d£2), 129.909d £2), 129.98 9d£2), 131.00 9s£2), 138.28
9s), 138.38 9s), 156.809d), 196.48 9s). High resolution
mass spectrum, m/z, 353.0912 9calcd for C20H19NOS2,
353.0908).
129.23 9d), 129.73 9d£2), 130.07 9d£2), 132.13 9s£2),
135.409d £2), 138.15 9s), 138.25 9s), 156.62 9d). MS m/z:
359 9M1). Anal. calcd for C22H17NS2´1/6H2O: C, 72.89; H,
4.82; N, 3.86. Found: C, 72.98; H, 4.83; N, 3.85. High
resolution mass spectrum, m/z, 359.0793 9calcd for
C20H19NOS2, 359.0803).
2.1.7. With sodium salt of diethyl malonate. NaCH-
9CO2Et)2 [prepared from diethyl malonate 9120mg,
0.75 mmol) and NaH 930.0 mg, 0.75 mmol) in dry THF
92 ml)] was added dropwise to a stirred suspension of 1
9175 mg, 0.50 mmol) in dry THF 92 ml) and the mixture
was stirred for 0.5 h. The work-up as above afforded diethyl
4,5-diphenyl-6H-1,2-thiazin-6-ylmalonate 3i 9190mg,
93%) as a brown oil, IR 9®lm, cm21): 17309CO), 1450
1
9NvCH). H NMR 9CDCl3) d: 1.04 93H, t, Jˆ7 Hz, Me),
1.3093H, t, Jˆ7 Hz, Me), 3.71 91H, d, Jˆ11 Hz, SCH),
3.75±3.84 91H, m, CH2), 3.91±3.99 91H, m, CH2), 4.18±
4.33 92H, m, CH2), 4.56 91H, d, Jˆ11 Hz, CHCO), 6.98±
7.39 910H, m, ArH), 8.28 91H, s, 3-H). 13C NMR 9CDCl3) d:
13.85 9q), 14.22 9q), 41.64 9d), 53.26 9d), 62.06 9t), 62.13 9t),
127.73 9d), 128.24 9d£3), 128.57 9s), 128.71 9d£2), 129.77
9d£2), 130.38 9d£2), 132.32 9s), 138.07 9s), 138.19 9s),
156.78 9d), 166.609s), 167.03 9s); High resolution mass
spectrum, m/z, 409.1344 9calcd for C23H23NO4S, 409.1348).
The reaction of 1 9175 mg, 0.50 mmol) with 1-ethylthio-1-
9trimethylsilyloxy)ethylene 9441 mg, 2.50mmol) in
CH2Cl2 91.5 ml) gave 3,6-bis[9ethylthio)carbonylmethyl]-
4,5-diphenyl-3,6-dihydro-2H-1,2-thiazine 4f 9132 mg, 58%)
as brown powders, mp 105±1088C 9dec.), IR 9KBr, cm21):
2.1.8. With sodium salt of acetylacetone. NaCH9COCH3)2
[prepared from acetylacetone 975 mg, 0.75 mmol) and NaH
930mg, 0.75 mmol) in dry THF 92 ml)] was added dropwise
to a suspension of 1 9175 mg, 0.50 mmol) in dry THF 92 ml)
at 08C. The work-up as above afforded 3-94,5-diphenyl-6H-
1,2-thiazin-6-yl)pentane-2,4-dione 3j 9180mg, quant.) as
white needles, mp 96±1008C, IR 9KBr, cm21): 17209CO),
14709N vCH). 1H NMR 9CDCl3) d: 1.76 93H, s, Me), 2.25
93H, s, Me), 4.24 91H, d, Jˆ11 Hz, 6-H), 4.62 91H, d, Jˆ
11 Hz, CHCO), 7.08±7.39 910H, m, ArH), 8.32 91H, s, 3-H).
13C NMR 9CDCl3) d: 29.31 9q), 31.64 9q), 41.86 9d), 69.41
9d), 127.85 9d), 128.47 9d), 128.63 9d£2), 128.84 9d£2),
129.64 9d£2), 130.46 9d£2), 130.50 9s), 132.29 9s), 137.34
9s), 138.31 9s), 157.33 9d), 201.32 9s), 201.64 9s). MS m/z:
349 9M1). Anal. calcd for C21H19NO2S: C, 72.18; H, 5.48;
N, 4.01. Found: C, 71.74; H, 5.73; N, 3.93.
1
3300 9NH), 1670 9CO). H NMR 9CDCl3) d: 1.19 93H, t,
Jˆ7 Hz, Me), 1.21 93H, t, Jˆ7 Hz, Me), 2.29 91H, dd, Jˆ16
and 2 Hz, 3-CHCHH), 2.69 91H, dd, Jˆ16 and 3 Hz, 6-CH±
CHH), 2.76±2.9094H, m, 2 £S-CH2Me), 2.95 91H, dd, Jˆ16
and 10Hz, 6-CHCH H), 3.34 92H, br. s and dd, Jˆ16 and
10Hz, NH and 3-CHCH H), 3.76 91H, dd, Jˆ10and 3 Hz,
6-H), 4.5091H, dd, Jˆ10and 2 Hz, 3-H), 6.93±6.96 94H, m,
ArH), 7.03±7.11 96H, m, ArH). 13C NMR 9CDCl3) d: 14.79
9q), 14.87 9q), 23.57 9t), 23.73 9t), 39.25 9d), 45.58 9t), 47.42
9t), 54.86 9d), 127.109d £2), 128.23 9d£2), 128.28 9d£2),
129.72 9d£2), 129.84 9d£2), 136.96 9s), 140.05 9s), 140.36
9s), 140.959s), 197.58 9s), 198.15 9s). MS m/z: 457 9M1).
Anal. calcd for C24H27NO2S3: C, 62.99; H, 5.95; N, 3.06.
Found: C, 62.82; H, 5.91; N, 3.01.
2.1.9. Reaction of 6-methoxy-4,5-diphenyl-6H-1,2-thia-
zine 3a with 70% HClO4. 70% HClO4 was added dropwise
to a solution of 3a 90.11 g, 0.41 mmol) in dry ether 912 ml)
at 08C and the reaction mixture was stirred for 20min. The
precipitates were collected by ®ltration and washed with
ether 95 ml£3) to give 1 90.11 g, 88%).
2.1.6. With sodium benzenethiolate. NaH 926.0mg,
0.64 mmol) was added to a solution of benzenethiol
957.0mg, 0.52 mmol) in dry THF 92 ml) and the mixture
was stirred for 0.5 h. This mixture was ice-cooled and added
dropwise to a stirred suspension of 1 9150mg, 0.43 mmol)
in dry THF 92 ml) at 08C. After stirring for 0.5 h, the reac-
tion mixture was poured into water and extracted with ether.
The extract was washed with water, and dried over MgSO4.
The solvent was evaporated under reduced pressure to leave
an oil, which was puri®ed by preparative TLC on silica gel
with hexane±ether 910:1) to afford 4,5-diphenyl-6-phenyl-
sulfanyl-6H-1,2-thiazine 3h 9118 mg, 77%) as pale yellow
prisms, mp 109±1118C 9dec.) 9from hexane±CH2Cl2). IR
2.1.10. Reaction of 4,5-diphenyl-6-1phenylsulfanyl)-6H-
1,2-thiazine 3h with SO2Cl2/70% HClO4. A solution of
SO2Cl2 983 mg, 0.61 mmol) in dry ether 95 ml) was added
dropwise to a solution of 3h 90.20 g, 0.56 mmol) in dry ether
910ml) at 0 8C. The reaction mixture was stirred for 10min
and then 70% HClO4 was added dropwise to the mixture.
The precipitates were collected by ®ltration and washed
with dry ether 95 ml£3) to give 1 90.15 g, 77%).
1
9KBr, cm21): 700 9CSC). H NMR 9CDCl3) d: 4.95 91H,
s, SCH), 7.07±7.10 92H, m, ArH), 7.15±7.26 96H, m, ArH),
7.28±7.52 95H, m, ArH), 7.64±7.72 92H, m, ArH), 8.16
91H, s, 3-H). 13C NMR 9CDCl3) d: 55.209d), 127.56 9s),
127.83 9d), 128.45 9d£2), 128.57 9d£3), 129.16 9d£2),
2.1.11. Reaction of 1 with 1,2,3-trimethoxybenzene. A
solution of 1 9150mg, 0.43 mmol) and 1,2,3-trimethoxy-
benzene 987.0mg, 0.52 mmol) in 1,2-dichloroethane
91.5 ml) was re¯uxed with stirring for 0.5 h. The solvent

H. Shimizu et al. / Tetrahedron 57 12001) 8965±8969
8969
was evaporated and the residue was subjected to preparative
TLC on silica gel with hexane±ethyl acetate 910:1) to afford
6-92,3,4-trimethoxyphenyl)-4,5-diphenyl-6H-1,2-thiazine
6a 956.0mg, 31%) as pale yellow prisms, mp 137±141 8C,
9from ether±CH2Cl2). IR 9KBr, cm21): 14709N vCH), 1100
9ether). 1H NMR 9CDCl3) d: 3.86 93H, s, OMe), 3.92 93H, s,
OMe), 4.01 93H, s, OMe), 4.98 91H, s, 6-H), 6.61 91H, d,
Jˆ9 Hz, ArH), 6.99 91H, d, Jˆ9 Hz, ArH), 7.02±7.14 97H,
m, ArH), 7.20±7.22 91H, m, ArH), 7.23±7.29 92H, m, ArH),
8.18 91H, s, 3-H). 13C NMR 9CDCl3) d: 39.35 9q), 56.15 9q),
61.00 9q), 61.49 9d), 106.80 9d), 122.98 9d), 126.53 9s),
127.809d), 128.23 9d £3), 128.75 9d£2), 129.08 9s),
129.72 9d£2), 130.18 9d£2), 132.55 9s), 139.12 9s), 139.58
9s), 142.94 9s), 150.67 9s), 153.87 9s), 155.04 9d). MS m/z:
417 9M1). Anal. calcd for C25H23NO3S: C, 71.92; H, 5.55;
N, 3.35. Found: C, 71.72; H, 5.68; N, 3.26.
SO2Cl2 980mg, 0.60mmol) in dry ether 93 ml) was added
dropwise to an ice-cooled solution of 3e 9200 mg,
0.54 mmol) in dry ether 98 ml) and the mixture was stirred
for 0.5 h. 70% HClO4 985.0mg, 0.60mmol) was added to
the mixture and the whole was stirred for 3 h. The reaction
mixture was concentrated and the residue was puri®ed by
the preparative TLC on silica gel with hexane±ethyl acetate
95:1) to afford 6-91-chlorophenacylidene)-6H-4,5-diphenyl-
1,2-thiazine 7 997.0mg, 58%) as an inseparable mixture of
two geometrical isomers 9E and Z isomers). The two
isomers were obtained in the ratio of 7:2, but each isomer
could not be assigned, mp 33±378C, red powders, IR 9KBr,
cm21): 16609CO). 1H NMR 9CDCl3) d: 6.65±6.72 93H, m,
ArH), 6.80±6.84 91H, m, ArH), 6.87±6.92 91H, m, ArH),
7.00±7.05 91H, m, ArH), 7.07±7.17 93H, m, ArH), 7.20±
7.27 92H, m, ArH), 7.34±7.47 93H, m, ArH), 7.67±7.69
91H, m, ArH), 8.19 91H, s, 3-H of one isomer), 8.54 91H,
1
2.1.12. Reaction of 1 with 1,2-dimethoxybenzene. A solu-
tion of 1 9150mg, 0.43 mmol) and 1,2-dimethoxybenzene
9118 mg, 0.88 mmol) in 1,2-dichloroethane 92 ml) was
re¯uxed with stirring for 0.5 h. The work-up as above
s, 3-H of the other isomer). FAB MS m/z: 40 2 9M11).
Anal. calcd for C24H16ClNOS: C, 71.72; H, 4.01; N, 3.49.
Found: C, 71.94; H, 4.22; N, 3.40.
2.1.15. 6-13,4-Dimethoxyphenyl)-4,5-diphenyl-1,2-thia-
zinylium perchlorate 11. A solution of SO2Cl2 967.0ml,
0.50 mmol) in dry ether 910 ml) was added dropwise to an
ice-cooled solution of 6b 9175 mg, 0.45 mmol) in dry ether
912 ml) at 08C and the mixture was stirred for 0.5 h. 70%
HClO4 971.0mg, 0.50mmol) was added dropwise to the
mixture, which was stirred for 3 h. The precipitated red
powders were ®ltrated and washed with dry ether
910ml £3) to give 6-93,4-dimethoxyphenyl)-4,5-diphenyl-
1,2-thiazinylium perchlorate 11 9222 mg, quant.) as red
powders, mp 208±2108C, IR 9KBr, cm21): 1100 9ClO42).
1H NMR 9CDCl3) d: 3.43 93H, s, OMe), 3.89 93H, s, OMe),
6.61 91H, d, Jˆ2 Hz, ArH), 6.89 91H, d, Jˆ8 Hz, ArH),
7.13±7.39 911H, m, ArH), 9.78 91H, s, 3-H). 13C NMR
9CDCl3) d: 56.14 9q), 56.45 9q), 111.809d), 112.44 9d),
122.63 9s), 125.08 9d), 129.01 9d£2), 129.08 9d£2),
129.71 9d), 130.26 9d£2), 130.62 9d£2), 130.87 9d),
132.11 9s), 135.25 9s), 149.75 9s), 150.61 9s), 151.58 9s),
153.96 9s), 163.77 9d), 189.59 9s). MS m/z: 386 9M12
ClO42). Anal. calcd for C24H20ClNO6S: C, 59.32; H, 4.15;
N, 2.88. Found: C, 58.76; H, 4.20; N, 2.86.
afforded 6-93,4-dimethoxyphenyl)-4,5-diphenyl-6H-1,2-
thiazine 6b 965.0mg, 39%) as pale yellow prisms, mp
139±1438C, 9from ether±CH2Cl2). IR 9KBr, cm21): 1520
9NvCH), 1030 9ether). H NMR 9CDCl3) d: 3.86 93H, s,
1
OMe), 3.88 93H, s, OMe), 4.56 91H, s, 6-H), 6.85 91H, d,
Jˆ9 Hz, ArH), 6.96±6.98 92H, m, ArH), 7.07±7.27 910H,
m, ArH), 8.19 91H, s, 3-H). 13C NMR 9CDCl3) d: 45.72 9q),
56.09 9q), 56.17 9d), 110.76 9d), 111.41 9d), 120.02 9d),
127.88 9d), 128.33 9d£2), 128.409d), 128.84 9d £2),
129.909d £2), 130.18 9d£2), 133.64 9s), 139.07 9s), 139.48
9s), 149.209s), 149.57 9s), 155.39 9d). MS m/z: 387 9M1).
Anal. calcd for C24H21NO2S´1/6H2O: C, 73.82; H, 5.51; N,
3.59. Found: C, 73.98; H, 5.65; N, 3.69. High resolution
mass spectrum, m/z, 387.1302 9calcd for C24H21NO2S,
387.1293).
2.1.13. Reaction of 1 with furan. A solution of 1 9150mg,
0.43 mmol) and furan 958.0 mg, 0.86 mmol) in dry MeCN
91 ml) was stirred at room temperature for 3 h. Ether was
added to the reaction mixture to afford 6-92-furyl)-4,5-
diphenyl-6H-1,2-thiazine 6c 963.0mg, 46%) as yellow
powders, mp 88±908C, IR 9KBr, cm21): 14509N vCH),
1010 9ether). 1H NMR 9CDCl3) d: 4.74 91H, s, 6-H),
6.28±6.3091H, m, ArH), 6.35 91H, dd, Jˆ1 and 2 Hz,
ArH), 7.01±7.21 97H, m, ArH) 7.23±7.34 93H, m, ArH),
7.47 91H, d, Jˆ1 Hz, ArH), 8.23 91H, s, 3-H). 13C NMR
9CDCl3) d: 40.30 9d), 109.70 9d), 111.05 9d), 127.32 9s),
127.94 9d), 128.409d £2), 128.57 9d), 128.81 9d£2),
129.92 9d£2), 130.20 9d£2), 131.47 9s), 138.73 9s), 138.82
9s), 143.609d), 151.83 9s), 156.05 9d). MS m/z: 317 9M1).
Anal. calcd for C20H15NOS´1/6H2O: C, 74.97; H, 4.82; N,
4.37. Found: C, 75.13; H, 4.82; N, 4.20. High resolution
mass spectrum, m/z, 317.0876 9calcd for C20H15NOS,
317.0874).
References
1. Shimizu, H.; Hatano, T.; Matsuda, T.; Iwamura, T. Tetrahedron
Lett. 1999, 40, 95±96.
2. Shimizu, H.; Hatano, T.; Iwamura, T. Tetrahedron Lett. 1999,
40, 1505±1508.
3. Lombardino, J. G. Nonsteroidal Antiin¯ammatory Drug; Wiley:
New York, 1985. Garigipati, R.; Cordova, R.; Parvez, M.;
Weinreb, S. M. Tetrahedron 1986, 42, 2979±2983. Bonacorso,
H. G.; Bittencourt, S. R. T.; Lourega, R. V.; Flores, A. F. C.;
Zanatta, N.; Martins, M. A. Synthesis 2000, 1431±1434.
2.1.14. Treatment of 6-phenacyl-4,5-diphenyl-6H-1,2-
thiazine 3e with SO2Cl2/70% HClO4. A solution of